CHICAGO — Family history plays a larger role in Barrett's esophagus and associated cancers than was previously recognized, according to Dr. Amitabh Chak.
“There's clearly an inheritance pattern that suggests an autosomal dominant disease,” said Dr. Chak at the annual Midwestern clinical research meeting.
Efforts to track down a genetic basis for Barrett's esophagus (BE) and related adenocarcinomas began with a cross-sectional pilot study in which Dr. Chak, a gastroenterologist at Case Western Reserve University, Cleveland, and his colleagues compared 56 patients with BE or adenocarcinoma of the esophagus or gastroesophageal junction with 106 controls who had gastroesophageal reflux.
“The Barrett's and esophageal cancer cases reported a positive family history for these diseases significantly more often than did the reflux controls,” Dr. Chak said at the meeting of the Central Society for Clinical Research and the Midwestern Section of the American Federation for Medical Research.
“That pilot study led us to formulate the more focused hypothesis that BE and associated cancers are complex genetic diseases with a combined underlying genetic and environmental cause. I think there's an inherited susceptibility to develop intestinal metaplasia, but that susceptibility may be present in only a subset of these patients who have this disease,” he said.
To test their hypothesis, the investigators went on a “gene hunt,” beginning with the endoscopic screening of relatives with BE or esophageal cancer. The breakthrough came with the identification of a large family with 13 affected members. The findings showed an inheritance pattern that suggested an autosomal dominant disease, Dr. Chak said.
With the help of investigators in the Familial Barrett's Esophagus Consortium, the Case Western team began to accumulate prospective data on affected families and published its first report on phenotype and demographics in 2004. They found endoscopy-identified esophageal cancer and BE in a substantial proportion of first-degree relatives of affected members of 69 families. In addition, a familial susceptibility to develop Barrett's epithelium appeared to be present in a subset of patients with BE and esophageal cancer (Am. J. Gastroenterol. 2004;99:2107–14).
The database, which has now grown to include 140 families, shows that 7.3% of 413 probands have a confirmed affected (with BE or esophageal cancer) first-degree or second-degree relative.
“We compared the risk factors for BE in familial and nonfamilial BE and esophageal cancer, and the main difference was that familial patients with cancer have a lower body mass index at diagnosis and at 1, 5, and 10 years before diagnosis,” he said, adding that familial Barrett's esophagus probands with cancer may be less obese and have shorter durations of obesity than those with apparently “sporadic” cancer.
The researchers currently are conducting linkage analysis to identify putative susceptibility genes and confirm their hypothesis. Meanwhile, Dr. Chak's recommendation is that all susceptible patients be screened endoscopically, which can be done relatively quickly and without sedation using an ultrathin endoscope.
Screening should include individuals with reflux who have two or more family members with Barrett's esophagus or esophageal cancer, one of whom is a first-degree relative (parent, sibling, or child), Dr. Chak said in an interview.
An unusual incidence of disease in second-degree relatives should raise suspicion, he added.